The airway epithelium plays an important role in the inflammatory response of the lung by the formation of bioactive molecules such as eicosanoids. In addition the epithelium serves as an air-liquid barrier for the trachea and bronchi and is a source of secretions including mucin which traps particles. Retinoids, which can markedly influence the differentiation state of the airway are essential for maintaining the muco-cilliary phenotype. The absence of retinoids leads to squamous metaplasia which is observed in several lung diseases. The major arachidonic acid metabolite was PGE2 for both phenotypes. No lipoxygenase metabolites were detected. Differentiated muco-cilliary cells produced high levels of PGE2 whereas differentiated squamous cells produced very low levels. Muco-cilliary cells expressed high levels of cPLA2 and PGHS-2 mRNA and protein. In contrast, squamous cells low levels of cPLA2 and PGHS-2 were detected. The PGHS-1 isoform was observed in the squamous but not in the muco-cilliary cells. Although the expression of cPLA2 and PGHS-2 expression was dependent on muco-cilliary differentiation, the formation of endogenous PGE2 was limited only by the expression cPLA2. Other data support the conclusion that the expression of cPLA2 and PGHS-2 is the result of differentiation and not the result of a direct effect of retinoic acid on the expression of these enzyme. Recently, the air-liquid interface system used to investigate differentiation of rat tracheal cells into squamous and muco-ciliary phenotype has been successfully extended to human bronchial eipthelial cells. Preliminary study of arachidonic acid metabolism indicated that the human cells poorly metabolize arachidonic acid to prostaglandins in contrast to the rat cells. Western and Northern analysis indicated the presence of high levels of the previously cloned human 15-lipoxygenase and low amounts of PGHS-1 and -2. Furthermore, PCR analysis confirmed the presence of human 15-lipoxygenase gene. Our future studies will focus on the human epithelial system.